1. Field of the Invention (Technical Field)
The present invention relates to C-terminus N-alkylated cyclic peptides that are agonists for the melanocortin-4 receptor (MC4-R), and which may be used in the treatment of sexual dysfunction and other conditions.
2. Description of Related Art
Note that the following discussion refers to a number of publications by author(s) and year of publication, and that due to recent publication dates certain publications are not to be considered as prior art vis-a-vis the present invention. Discussion of such publications herein is given for more complete background and is not to be construed as an admission that such publications are prior art for patentability determination purposes.
Melanocortin Receptors.
A family of melanocortin receptor types and subtypes have been identified, including melanocortin-1 receptors (MC1-R) expressed on normal human melanocytes and melanoma cells, melanocortin-2 receptors (MC2-R) for ACTH (adrenocorticotropin) expressed in cells of the adrenal gland, melanocortin-3 and melanocortin-4 receptors (MC3-R and MC4-R) expressed primarily in cells in the hypothalamus, mid-brain and brainstem, and melanocortin-5 receptors (MC5-R), expressed in a wide distribution of peripheral tissues.
Significant work has been done in determining the structure of melanocortin receptors, including both the nucleic acid sequences encoding for the receptors and the amino acid sequences constituting the receptors. MC4-R is a G protein-coupled, 7-transmembrane receptor that is believed to be expressed primarily in the brain. Inactivation of this receptor by gene targeting has been reported to result in mice with the maturity-onset obesity syndrome that is associated with hyperphagia, hyperinsulinemia, and hyperglycemia (Huszar D, Lynch C A, Fairchild-Huntress V, et al. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 88:131-141, 1997). MC4-R is a molecular target for therapeutic intervention in energy homeostasis.
Compounds specific for MC4-R, and secondarily compounds specific for MC3-R or MC5-R, are believed to be useful in regulation of mammalian energy homeostasis, including use as agents for attenuating food intake and body weight gain. MC4-R agonists are believed to be useful for treating sexual dysfunction, including male erectile dysfunction, and for decreasing food intake and body weight gain, such as for treatment of obesity. Such compounds may also be employed for treatment of depression and related disorders, decreasing voluntary ethanol consumption, and the like. MC4-R antagonists, by contrast, are believed to be useful for weight gain aid, such as for use in treatment of cachexia, sarcopenia, wasting syndrome or disease, and anorexia.
Sexual Dysfunction.
Sexual dysfunction, including both penile erectile dysfunction or impotence and female sexual dysfunction, is a common medical problem. Significant effort has been devoted over the last twenty or more years to develop methods, devices and compounds for treatment of sexual dysfunction. While more effort has been undertaken for treatment of penile erectile dysfunction, female sexual dysfunction is also an area to which significant research and effort has been devoted.
At present, commonly used orally administered drugs for treatment of sexual dysfunction in the male are phosphodiesterase 5 (PDE-5) inhibitors, increasing the persistence of cyclic guanosine monophosphate and thereby enhancing erectile response. Such drugs include Viagra®, a brand of sildenafil, Levitra®, a brand of monohydrochloride salt of vardenafil, and Cialis®, a brand of tadalafil. Another drug approved in Europe for treating male erectile dysfunction is Ixense®, a brand of apomorphine that is a non-selective dopa receptor agonist. Oral and nasal formulations of apomorphine have undergone clinical evaluation. There are several other medical treatment alternatives currently available depending on the nature and cause of the impotence problem. Some men have abnormally low levels of the male hormone testosterone, and treatment with testosterone injections or pills may be beneficial. However, comparatively few impotent men have low testosterone levels. For many forms of erectile dysfunction, treatment may be undertaken with drugs injected directly into the penis, including drugs such as papaverin, prostaglandin E1, phenoxybenzamine or phentolamine. These all work primarily by dilating the arterial blood vessels and decreasing the venous drainage. Urethral inserts, such as with suppositories containing prostaglandin, may also be employed. In addition, a variety of mechanical aids are employed, including constriction devices and penile implants.
A number of other agents have been shown to induce or facilitate penile erection in laboratory animals. These include very diverse classes of ligands such as oxytocin (Benelli A., Poggioli R., Luppi P., Ruini L., Bertolini A., Arletti R., Oxytocin enhances, and oxytocin antagonism decreases, sexual receptivity in intact female rats. Neuropeptides 27:245-50 (1994)), vasopressin, vasoactive intestinal peptide, melanotropins, and ACTH as well as their analogs.
A variety of treatments have also been explored for female sexual dysfunction, including use of sildenafil, although the Food and Drug Administration has not specifically approved such use. Testosterone propionate has also been employed to increase or augment female libido.
Melanocortin Agonist Peptides.
Melanocortin receptor-specific compounds have been explored for use of treatment of sexual dysfunction. In one report, a cyclic α-melanocyte-stimulating hormone (“α-MSH”) analog, Ac-Nle-cyclo(-Asp-His-D-Phe-Arg-Trp-Lys)-NH2, was evaluated for erectogenic properties for treatment of men with erectile dysfunction. Wessells H. et al., J Urology 160:389-393 (1998); see also U.S. Pat. No. 5,576,290, issued Nov. 19, 1996 to M. E. Hadley, entitled Compositions and Methods for the Diagnosis and Treatment of Psychogenic Erectile Dysfunction and U.S. Pat. No. 6,051,555, issued Apr. 18, 2000, also to M. E. Hadley, entitled Stimulating Sexual Response in Females. The peptides used in U.S. Pat. Nos. 5,576,290 and 6,051,555 are also described in U.S. Pat. No. 5,674,839, issued Oct. 7, 1997, to V. J. Hruby, M. E. Hadley and F. Al-Obeidi, entitled Cyclic Analogs of Alpha-MSH Fragments, and in U.S. Pat. No. 5,714,576, issued Feb. 3, 1998, to V. J. Hruby, M. E. Hadley and F. Al-Obeidi, entitled Linear Analogs of Alpha-MSH Fragments.
Additional related peptides are disclosed in U.S. Pat. Nos. 5,576,290, 5,674,839, 5,714,576 and 6,051,555. These peptides are described as being useful for both the diagnosis and treatment of psychogenic sexual dysfunction in males and females. These peptides are related to the structure of melanocortins. Other peptides are disclosed in U.S. Pat. No. 6,284,735 and U.S. Published Patent Applications Nos. 2001/0056179 and 2002/0004512.
The peptide Ac-Nle-cyclo(-Asp-His-D-Phe-Arg-Trp-Lys)-OH is disclosed in U.S. Pat. No. 6,579,968, issued Jun. 17, 2003, and U.S. Pat. No. 6,794,489, Sep. 21, 2004, and is employed for treatment of erectile dysfunction and female sexual dysfunction.
It is believed that erectile response to melanocortin receptor-specific compounds, and both male and female sexual response in general, is at least in part related to the central tetrapeptide sequence, His6-Phe7-Arg8-Trp9 (SEQ ID NO:1) of native α-MSH. In general, all natural melanocortin peptides share the same active core sequence, His-Phe-Arg-Trp (SEQ ID NO:1), including melanotropin neuropeptides and adrenocorticotropin. While the mechanism of His-Phe-Arg-Trp (SEQ ID NO:1) induction of erectile response has not been fully elucidated, it is generally accepted that it involves the central nervous system, and binding to MC3-R and/or MC4-R, and according to most researchers, MC4-R.
Both cyclic and linear α-MSH peptides have been studied for sexual dysfunction; however, the peptides heretofore evaluated have had an —NH2 group at the C-terminus, or, as in the case of Ac-Nle-cyclo(-Asp-His-D-Phe-Arg-Trp-Lys)-OH, an —OH group.
In certain aspects, this application is related to U.S. patent application Ser. No. 11/174,845, filed Jul. 5, 2005, entitled “Cyclic Peptides for Treatment of Cachexia”, to Shubh D. Sharma, et al., which claimed priority to U.S. Provisional Patent Application Ser. No. 60/585,971, entitled “Cyclic Peptides for Treatment of Cachexia”, to Shubh D. Sharma, et al.; and to U.S. patent application Ser. No. 10/638,071, filed Aug. 8, 2003, entitled “Cyclic Peptide Compositions and Methods for Treatment of Sexual Dysfunction”, to Shubh D. Sharma, et al., which is a continuation-in-part of International Application No. PCT/US02/22196, International Publication No. WO 03/006620, filed on Jul. 11, 2002, entitled “Linear and Cyclic Melanocortin Receptor-Specific Peptides”, to Shubh D. Sharma, et al., which claimed priority to U.S. Provisional Patent Application Ser. No. 60/304,836, entitled “Linear and Cyclic Melanocortin Receptor-Specific Peptides”, filed on Jul. 11, 2001, and the specification and claims thereof of each are incorporated herein by reference.